Some patients with idiopathic pulmonary fibrosis (IPF), a progressive fibroproliferative lung disease of older adults, develop sudden acute exacerbations (AE-IPF) that can result in respiratory failure and death within days. Steroids are standard treatment for AE-IPF, although these and all other medical therapies tried to date have been ineffectual. Findings of our research group, as well as others, show that numerous immune abnormalities that are identical to conventional autoantibody-mediated syndromes are also common in IPF patients, especially among those who are having or will soon have acute exacerbations. An autoimmune pathogenesis could also explain the refractoriness of AE-IPF to current therapy, since many conventional autoantibody-mediated lung diseases are also resistant to treatment with steroids and other nonspecific agents. However, regimens that specifically reduce preexisting autoantibodies, deplete autoantibody-producing B-cells, and/or inhibit B-cell autoantibody production are more often beneficial for these syndromes. We have conducted a proof-of-concept pilot trial in which seriously-ill AE-IPF patients were treated with therapeutic plasma exchange (TPE) to very rapidly reduce circulating autoantibodies, plus rituximab to deplete autoantibody-producing B-cells, plus intravenous immunoglobulin (IVIG) to further inhibit auto- antibody production. In comparisons to a historical control group, these autoantibody reduction therapies resulted in unprecedented clinical responses in most AE-IPF patients. Accordingly, we hypothesize: AUTOANTIBODY REDUCTION IS BENEFICIAL FOR AE-IPF PATIENTS. We propose here a randomized Phase IIb clinical trial to test this hypothesis by comparing efficacy of TPE plus rituximab plus IVIG vs. treatment as usual (TAU) for AE-IPF patients. After providing informed consent, subjects hospitalized for AE-IPF at five participating medical centers will be randomized (2:1) to either the experimental arm or TAU, respectively. The primary endpoint of this trial is six-month survival. Secondary endpoints include changes in requirements for supplemental oxygen and six-minute walk distances, as well as adverse events rates. We anticipate this innovative experimental treatment will result in improved survival, lesser oxygen requirements, greater functional capacities, and an acceptable toxicity profile. Additional translational studies will examine the potential clinical use of autoantibody assays in AE- IPF patients. Results of this investigation could substantially alter treatment approaches, and save the lives of future patients who have this rapidly progressive and too-often lethal lung disease.